title: Discovery and SAR of spirochromane Akt inhibitors.
abstract: A novel series of spirochromane pan-Akt inhibitors is reported. SAR optimization furnished compounds with improved enzyme potencies and excellent selectivity over the related AGC kinase PKA. Attempted replacement of the phenol hinge binder provided compounds with excellent Akt enzyme and cell activities but greatly diminished selectivity over PKA.
authors.affiliation: Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, USA. nkallan@arraybiopharma.com
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Kallan
authors.forename: Keith L
authors.initials: KL
authors.lastname: Spencer
authors.forename: James F
authors.initials: JF
authors.lastname: Blake
authors.forename: Rui
authors.initials: R
authors.lastname: Xu
authors.forename: Justin
authors.initials: J
authors.lastname: Heizer
authors.forename: Josef R
authors.initials: JR
authors.lastname: Bencsik
authors.forename: Ian S
authors.initials: IS
authors.lastname: Mitchell
authors.forename: Susan L
authors.initials: SL
authors.lastname: Gloor
authors.forename: Matthew
authors.initials: M
authors.lastname: Martinson
authors.forename: Tyler
authors.initials: T
authors.lastname: Risom
authors.forename: Stefan D
authors.initials: SD
authors.lastname: Gross
authors.forename: Tony H
authors.initials: TH
authors.lastname: Morales
authors.forename: Wen-I
authors.initials: WI
authors.lastname: Wu
authors.forename: Guy P A
authors.initials: GP
authors.lastname: Vigers
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Brandhuber
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Skelton
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt